Absence of Hyperactivation of Fibrinolysis Explains the Lack of Hemostatic Efficacy of Prophylactic Tranexamic Acid (TXA) in Hypoproliferative Thrombocytopenia

Abstract Background: We previously reported the results of the A-TREAT study (American Trial Using Tranexamic Acid in Thrombocytopenia: NCT02578901). This randomized double-blind placebo-controlled trial demonstrated that TXA administration is not superior to placebo in preventing WHO grade 2 or higher bleeding in severely thrombocytopenic patients requiring supportive platelet transfusion following myeloablative therapy for hematologic disorders (Gernsheimer T., ASH 2020 Plenary Session). Here, we present results of the A-TREAT ancillary study - Fibrinolysis Evaluation in A-TREAT (FEAT). Blood samples were collected from a subset (n=115) of A-TREAT participants just prior to initiation of study drug (when the platelet count was <30,000/µl) and at a later time point when TXA was at a steady state trough level (5 ±2 days following study drug initiation). Using global assays of fibrinolysis in plasma, our a priori hypotheses were that: 1] a baseline 'hyperfibrinolytic' profile would be associated with a higher proportion of grade 2+ bleeding; and 2] trough TXA levels would be associated with a 'hypofibrinolytic' profile and a lower proportion of grade 2+ bleeding. Methods: Fibrinolysis in platelet-free citrated plasma was assessed by 3 global assays: euglobulin clot lysis time (ECLT), plasmin generation (PG), and tPA resistance clot lysis time (tPA-CLT) using previously described methods (Ilich A. RPTH 2020, Miszta A. JTH 2021). Trough plasma TXA concentration was measured using a validated tandem mass spectrometry assay. Individual fibrinolytic analytes (PAI-1, tPA, plasminogen, alpha2-antiplasmin and plasmin-antiplasmin complexes) were quantified by ELISA. Results: Baseline samples did not demonstrate a hyperfibrinolytic profile by ECLT. To the contrary, ECLT values were significantly increased compared to healthy controls (figure 1). Furthermore, none of the measured fibrinolytic parameters (ECLT, tPA-CLT, total PAI-1, tPA, plasminogen, alpha2-antiplasmin or plasmin-antiplasmin complexes) at baseline were associated with a greater risk of grade 2+ bleeding during follow up, regardless of treatment arm. On the follow-up samples, neither pharmacokinetic (trough TXA concentration) nor pharmacodynamic parameters (PG or tPA-CLT) were associated with bleeding severity. A high inter-patient variability of TXA trough concentrations was noted in the treatment arm (min-max: 0.7-10 ug/ml), and drug levels correlated strongly with global fibrinolysis assessment by PG (Spearman r, -0.78, 95% CI -0.88 - -0.62) and tPA-CLT (r, 0.74, 0.56 - 0.85) (figure 2). Conclusions: 1] No evidence of fibrinolytic hyperactivation was observed in these thrombocytopenic patients; 2] trough TXA concentrations varied significantly between patients receiving the same dosing schedule; and 3] tPA-CLT and PG parameters correlated well with TXA plasma concentrations and thus may be used to estimate the extent of fibrinolytic inhibition in patients treated with TXA. Discussion: The absence of hyperactivation of endogenous fibrinolysis in this study is in contrast to our recent findings in trauma. Specifically, we reported that almost half of trauma patients demonstrated evidence of fibrinolytic hyperactivation (by ECLT) on admission (Ilich A. Thromb Res, 2021). Since TXA has been shown to reduce mortality due to bleeding in trauma (CRASH II, Lancet, 2010) and given that baseline hyperfibrinolysis is common in trauma, we hypothesize that the absence of fibrinolytic hyperactivation observed in the A-TREAT study patients likely explains the clinical lack of efficacy of TXA. Figure 1 Figure 1. Disclosures Gernsheimer: Amgen: Honoraria; Novartis: Honoraria; Principia: Research Funding; Rigel: Research Funding; Cellphire: Consultancy; Dova: Consultancy; Sanofi: Consultancy. Triulzi: Fresenius Kabi: Membership on an entity's Board of Directors or advisory committees; Realta: Membership on an entity's Board of Directors or advisory committees. Wolberg: CSL Behring: Consultancy; Bristol Myers Squibb: Research Funding; Takeda: Research Funding. Key: Takeda: Research Funding; BioMarin: Honoraria, Other: Participation as a clinical trial investigator; Sanofi: Consultancy; Grifols: Research Funding; Uniqure: Consultancy, Other: Participation as a clinical trial investigator.

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Romiplostim in Thrombocytopenic Patients with Low- or Int-1- Risk MDS Results in Reduced Bleeding without Impacting Leukemic Progression: Final Follow-up Results from a Randomized, Double-Blind, Placebo-Controlled Study

Blood ◽

10.1182/blood.v128.22.2000.2000 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2000-2000

Author(s):

Hagop Kantarjian ◽

Pierre Fenaux ◽

Mikkael A. Sekeres ◽

Jeffrey Szer ◽

Uwe Platzbecker ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Controlled Study ◽

Bleeding Events ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: Thrombocytopenia occurs in ~50% of patients with low/int-1 risk myelodysplastic syndrome (MDS) and is associated with reduced survival. In a placebo (PBO)-controlled study, 250 patients with MDS were randomized 2:1 to receive weekly romiplostim or PBO. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events [hazard ratio (HR) romiplostim vs PBO 0.83, 95% CI: 0.66−1.05, P = 0.13] and platelet transfusions (relative risk 0.77, 95% CI: 0.66−0.88, P<0.001) and increased IWG hematologic improvement platelets (HI-P) incidence (odds ratio 15.6, 95% CI: 4.7−51.8, P<0.001). Peripheral blast count increases >10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.6%) and resolved after discontinuation in most cases. In February 2011, the DMC recommended that treatment with study drug be discontinued as the potential benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML, and that transient increases in blast cell counts might put patients at risk for diagnosis of and treatment for AML. Patients were moved into long-term follow-up (LTFU). Previously reported (Giagounidis et al, Cancer 2014) 58-week incidence of AML was 6.0% (N = 10) for romiplostim and 4.9% for PBO (N = 4); HR 1.20 (95% CI: 0.38−3.84). This report provides final 5-year LTFU data. Methods: Eligible patients were receiving only supportive care and had IPSS low/int-1 risk MDS and platelets 1) ≤20 × 109/L or 2) ≤50 × 109/L with a history of bleeding. Disease progression to AML was defined as 1) ≥20% blasts in bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim; 2) pathology consistent with leukemia; or 3) antileukemic treatment. Results are presented by treatment group. Results: At baseline, median (Q1, Q3) age was 70 (61, 77) years, the majority (59%) of patients were male; 27.6% were IPSS low risk and 72.4% were int-1 risk. WHO classifications were RCMD: 67.6%, RAEB-1: 13.2%, MDS-U: 11.2%, RA: 4.4%, RCMD-RS: 2.4%, RARS: 0.8%, and RAEB-2: 0.4%. Of 250 patients in the study, 210 entered LTFU and 66 completed the 5 years of LTFU; median (Q1, Q3) follow-up was 27.5 (10.8, 58.7) months. Reasons for discontinuation (death, lost to follow-up, and consent withdrawal) during LTFU were similar in both groups. During the active study period and LTFU, death was reported in 93 (55.7%) patients in the romiplostim group and 45 (54.2%) patients in the PBO group (HR romiplostim vs PBO 1.03, 95% CI: 0.72−1.47) (Figure); mortality rates were greater in those with IPSS int-1 vs low risk for both groups (Table). AML was reported in 20 (11.9%) patients in the romiplostim group and 9 (11.0%) patients in the PBO group (HR 1.06, 95% CI: 0.48−2.33). The proportions of patients who either died or developed AML were 56.9% (N = 95) in the romiplostim group and 55.4% (N = 46) in the PBO group (HR for AML-free survival 1.04, 95% CI: 0.73−1.48) (Figure). Nearly half (N = 14, 48%) of the 29 AML cases occurred in patients who were RAEB-1 at screening (none RAEB-2), and 6 cases were diagnosed because of anti-AML treatment use alone (Table). In LTFU, patient-reported use of MDS therapy (eg, azacitidine or cyclosporine) was 42.8% (N = 59, 95% CI: 34.4%−51.5%) in the romiplostim group and 31.4% (N = 22, 95% CI: 20.9%−43.6%) in the PBO group. AML therapy (eg, chemotherapy) was used in 14 (10.2%) patients in the romiplostim group and 7 (10.0%) patients in the PBO group. Conclusions: Following the decision in 2011 to stop study drug secondary to increased AML rates at that time and transient blasts increases, final 5-year LTFU HRs (romiplostim vs placebo) for death or progression to AML, respectively, are 1.03 (95% CI: 0.72−1.47) and 1.06 (95% CI: 0.48−2.33). In conclusion, romiplostim reduced bleeding events and platelet transfusions, with no increase in AML incidence or impact on survival. Disclosures Kantarjian: Amgen Inc.: Research Funding. Fenaux:Amgen Inc.: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kuendgen:Celgene: Research Funding. Gaidano:Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wiktor-Jedrzejczak:Angelini: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy, Research Funding; BMS: Research Funding; Sandoz: Consultancy; Amgen Inc.: Research Funding. Carpenter:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.

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Long-Term Follow-up of Patients with Mantle Cell Lymphoma Treated with Venetoclax Monotherapy

Blood ◽

10.1182/blood-2018-99-117210 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2883-2883

Author(s):

Matthew S. Davids ◽

Andrew W. Roberts ◽

William G. Wierda ◽

Kathryn Humphrey ◽

Debbie J Alter ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progressive Disease ◽

Response Rate ◽

Study Drug ◽

Employment Equity ◽

Advisory Committees ◽

Mantle Cell ◽

Equity Ownership

Abstract Introduction: Venetoclax is a selective, oral inhibitor of BCL2, a key regulator of the intrinsic apoptotic pathway. The dose-escalation phase 1 study of venetoclax in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) enrolled 106 patients from June 2011, and the overall response rate across the entire NHL cohort was 44%. The highest response rate (75%) was seen in the 28 patients with mantle cell lymphoma (MCL) (Davids et al., J Clin Oncol. 2017). Here, we report longer-term outcomes for those patients, now with a median of 27 months (range: 0.2 - 59) follow up. Methods: Venetoclax was administered in dose cohorts ranging from a maximum dose of 300-1200 mg and continued until progressive disease (PD) or unacceptable toxicity; intra-patient dose escalation was allowed. Adverse events (AEs) were assessed by NCI-CTCAE v4.0 and responses were assessed using 2007 Cheson IWG response criteria, utilizing CT scans beginning at week 6. The data cut off for this analysis was June 4th, 2018. Results: For the 28 patients with MCL, the median age was 72 years (range: 35 - 85). They had received a median of 3 (range: 1 - 7) prior treatments; 5 patients received prior PI3K inhibitor (but no prior ibrutinib). The median time from the preceding treatment to start of venetoclax was 13 months (range: 2 - 148). The median dose of venetoclax was 400 mg/day; 25/28 received at least 400mg/day. Median time on study drug was 11 months (range: 0.2 - 59). Three patients have been on therapy for over 4 years. The overall response rate was 75%, with 6 (21%) patients achieving complete remission (CR) and 15 (54%) partial response (PR). The median duration of response was 16 months (95% CI: 4, 30) and median progression free survival was 11 months (95% CI: 5, 21) for all patients (Figure). The 2 year PFS estimate was 30% (95% CI: 14%, 47%) for all patients, 83% (95% CI: 27%, 97%) for patients who achieved CR and 14% (95% CI: 2%, 37%) for patients who achieved PR. One patient who achieved PR proceeded to allogeneic stem cell transplant and remained disease free at the last protocol defined follow-up (24 months after coming off study). Three patients developed progressive disease after receiving venetoclax for more than two years of therapy (time to progression: 31, 33, and 33 months). Two patients with CR continue on study without evidence of progression, currently at 47 and 59 months of venetoclax monotherapy. The most common (≥25% of patients with MCL) all grade treatment emergent AEs were nausea (57%), diarrhea (50%), fatigue (39%), constipation (29%) and upper respiratory infection (25%). The most common (≥10% of patients with MCL) grade 3/4 AEs were neutropenia (14%), anemia (14%), pneumonia (11%), and thrombocytopenia (11%). Biochemical tumor lysis syndrome (TLS), without accompanying clinical features, was reported in one patient considered high risk for TLS. Specific interventions were not required, and the patient continued on study drug. Conclusions: Venetoclax monotherapy leads to durable remission in a meaningful proportion of patients with pretreated MCL. Further studies in MCL are currently investigating potential biomarkers for durable response to venetoclax combination regimens, including a Phase 3 randomized study with ibrutinib (SYMPATICO, NCT03112174). Disclosures Davids: Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Merck: Consultancy; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding. Roberts:Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Alter:AbbVie, Inc: Employment, Equity Ownership. Masud:AbbVie, Inc: Employment, Equity Ownership. Buss:Abbvie, Inc: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Seymour:Janssen: Honoraria, Research Funding; Celgene: Consultancy; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding.

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Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3 Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura

Blood ◽

10.1182/blood.v130.suppl_1.lba-1.lba-1 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. LBA-1-LBA-1 ◽

Cited By ~ 1

Author(s):

Marie Scully ◽

Spero R Cataland ◽

Flora Peyvandi ◽

Paul Coppo ◽

Paul Knöbl ◽

...

Keyword(s):

Platelet Count ◽

Drug Treatment ◽

Board Of Directors ◽

Treatment Period ◽

Research Funding ◽

Thromboembolic Event ◽

Study Drug ◽

Adamts13 Activity ◽

Advisory Committees

Abstract Introduction: Acquired or immune-mediated thrombotic thrombocytopenic purpura (aTTP) is a life-threatening thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. Inhibitory autoantibodies cause a severe deficiency of the von Willebrand factor (vWF) cleaving enzyme ADAMTS13, leading to intravascular vWF-platelet aggregation and microvascular thrombosis. The mainstays of treatment are plasma exchange (PE) and immunosuppression. Caplacizumab, a bivalent Nanobody, targets the A1 domain of vWF, inhibiting the interaction between ultra-large vWF and platelets. Methods: Patients with an acute episode of aTTP who had received one PE treatment were randomized 1:1 to placebo or 10 mg caplacizumab, in addition to daily PE and corticosteroids. A single IV dose of study drug was given before the first on-study PE and a SC dose was given daily during the PE period and 30 days thereafter. If at the end of this period there was evidence of ongoing disease, such as suppressed ADAMTS13 activity, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks together with optimization of immunosuppression. All patients entered a 28-day treatment-free follow up period after the last dose of study drug (Figure 1). Primary endpoint was time to platelet count response, defined as platelet count ≥ 150×109/L with stop of daily PE within 5 days. There were 4 key secondary endpoints, hierarchically ranked. The 1st was a composite of aTTP-related death, aTTP recurrence, or major thromboembolic event during the study drug treatment period. A blinded, independent committee adjudicated aTTP-related deaths and major thromboembolic events. The 2nd looked at recurrences during the entire study period, including the follow up period. The 3d evaluated refractoriness to therapy, defined as absence of platelet count doubling after 4 days of treatment and LDH still above normal. The 4th was the time to normalization of 3 organ damage markers: LDH, cardiac troponin I and serum creatinine. Results: 145 patients were randomized, 73 to placebo and 72 to caplacizumab. Demographics and baseline disease characteristics were balanced between groups, except for a higher proportion of initial episodes in the caplacizumab arm. Compared to patients treated with placebo, those on caplacizumab were >50% more likely to achieve a platelet response at any given time point (platelet count normalization rate 1.55, 95% CI 1.10 - 2.20, p <0.01). During the study drug treatment period, treatment with caplacizumab resulted in a 74% reduction in TTP-related death, recurrence of TTP, or a major thromboembolic event (p <0.0001, Table 1). During the overall study period, 28 patients in the placebo group experienced a recurrence versus 9 patients in the caplacizumab group, a 67% reduction (p <0.001, Table 2). In all 6 caplacizumab-treated patients with a relapse during the follow up period, ADAMTS13 activity was still <10% at stop of study drug, reflecting ongoing disease. No caplacizumab-treated patients were refractory to therapy, while 3 patients on placebo were (p =0.057). Treatment with caplacizumab was associated with a trend toward faster normalization of the 3 organ damage markers. Safety is summarized in Table 3. In the caplacizumab group, the most common study drug-related TEAEs were epistaxis, gingival bleeding, and bruising. During the study drug treatment period, 3 patients on placebo died. One death occurred during the follow up period in a caplacizumab-treated patient and was assessed by the investigator as not related to study drug. Conclusions: Results of the Phase 3 HERCULES study confirm that treatment with caplacizumab reduces the time to platelet count response, resulting in faster resolution of aTTP. Treatment with caplacizumab also resulted in a highly clinically meaningful reduction in aTTP-related death, recurrence of aTTP, or a major thromboembolic event during study drug treatment. The relapses after stop of study drug in patients with ADAMTS13 activity <10% suggest that treatment should be continued until complete resolution of the underlying disease. Caplacizumab has a favorable safety profile, with mucocutaneous bleeding the most frequently reported AE. Caplacizumab, through rapid blocking of vWF-mediated platelet aggregation, represents a novel treatment option for patients with aTTP. (clinicaltrials.gov: NCT02553317) Disclosures Scully: Ablynx: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Novartis: Honoraria; Alexion: Honoraria. Cataland:Ablynx NV: Membership on an entity's Board of Directors or advisory committees. Peyvandi:Ablynx, Roche: Membership on an entity's Board of Directors or advisory committees; Ablynx, Bayer, Grifols, Novo Nordisk, Sobi: Speakers Bureau;Freeline, Kedrion, LFB, Octapharma: Consultancy. Coppo:Ablynx: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Knöbl:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Kremer Hovinga:Baxalta/Shire: Other: unrestricted grant hereditary TTP registry; Ablynx NV: Membership on an entity's Board of Directors or advisory committees. Metjian:Ablynx NV, Shire, Omeros: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Other: Honoraria; Celgene: Other: Honoraria; Janssen: Other: Honoraria. Pavenski:Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria; Ablynx: Other: participation in industry sponsored RCT; CSL Behring: Research Funding. Callewaert:Ablynx NV: Employment. Biswas:Ablynx NV: Employment. De Winter:Ablynx NV: Employment. Zeldin:Ablynx NV: Employment.

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Treatment with the Thrombopoietin (TPO)-Receptor Agonist Romiplostim in Thrombocytopenic Patients (Pts) with Low or Intermediate-1 (int-1) Risk Myelodysplastic Syndrome (MDS): Follow-up AML and Survival Results of a Randomized, Double-Blind, Placebo (PBO)-Controlled Study

Blood ◽

10.1182/blood.v120.21.421.421 ◽

2012 ◽

Vol 120 (21) ◽

pp. 421-421 ◽

Cited By ~ 7

Author(s):

Hagop M. Kantarjian ◽

Ghulam J. Mufti ◽

Pierre Fenaux ◽

Mikkael A. Sekeres ◽

Jeffrey Szer ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Survival Rates ◽

Study Drug ◽

Employment Equity ◽

Advisory Committees ◽

Free Survival ◽

Equity Ownership

Abstract Abstract 421 Background: There are few therapies for thrombocytopenia in MDS, which is found in ∼50% of pts with low/int-1 MDS and is associated with shortened survival. In a June 2011 analysis of a 58-wk study (2:1 romiplostim:PBO), romiplostim reduced clinically significant bleeding events (HR 0.83, 95% CI: 0.66, 1.05, P = 0.13) and platelet transfusions (RR 0.77, 95% CI: 0.66, 0.88), and increased HI-P rates (OR 15.6, 95% CI: 4.7, 51.8). Increases in peripheral blast counts to >10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.6%), and in most cases resolved after discontinuation. Through 58 wk, acute myeloid leukemia (AML) was diagnosed in 10 romiplostim pts (6.0%) and 2 PBO pts (2.4%) (HR 2.51, 95% CI: 0.55, 11.47); the differences for romiplostim vs. PBO 58-wk overall survival (OS) and AML-free survival were not statistically significant. This report updates the previous results, with a particular emphasis on AML incidence. Methods: Eligible pts had IPSS low/int-1 MDS and were receiving supportive care, with platelets 1) ≤20×109/L or 2) ≤ 50×109/L with a history of bleeding. AML progression was defined as: 1) ≥20% blasts in the bone marrow or peripheral blood after 4 wk off romiplostim, 2) pathology consistent with leukemia (eg, chloroma or leukemia cutis), or 3) anti-leukemic treatment initiation. Due to data monitoring committee concerns that the potential small benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML and that transient increases in blast cell counts may put pts at risk for diagnosis of and treatment for AML, study drug was stopped in February 2011. Pts were then moved into the long-term follow-up (LTFU) portion of the study. At the time of the 2011 analysis, not all pts had been on study 58 wk, thus the 58-wk data have been updated with LTFU data. Results: Results are presented by randomization group, although study drug was stopped in February 2011. Of 250 pts in the study (randomized 2:1 romiplostim:PBO), 224 entered LTFU, and 134 remained on study as of July 2012; the median (Q1, Q3) follow-up was 17.8 (10.8, 25.1) months. Through 58 wk, the proportions of deaths were romiplostim: 18.0% (30 pts), PBO: 20.5% (17 pts), for an OS HR of 0.86 (95% CI: 0.48, 1.56). Since June 2011, 2 additional AML cases were reported in the PBO arm which occurred within the 58-wk study period, but were not recorded in time for the primary analysis in 2011. Updated 58-wk AML rates were romiplostim: 6.0% (10 pts), PBO: 4.9% (4 pts), for an HR of 1.20 (95% CI: 0.38, 3.84). The resulting AML-free survival rates were romiplostim: 19.8% (33 pts), PBO: 22.9% (19 pts), for an HR of 0.86 (95% CI: 0.49, 1.51). For data to date (beyond 58 wk), proportions of deaths were romiplostim: 38.3% (64 pts), PBO: 37.3% (31 pts), for an OS HR of 1.09 (95% CI: 0.71, 1.68). AML rates were romiplostim: 8.9% (15 pts), PBO: 8.5% (7 pts), for an HR of 1.15 (95% CI: 0.47, 2.85). The resulting AML-free survival rates were romiplostim: 39.5% (66 pts), PBO: 38.6% (32 pts), for an HR of 1.11 (95% CI: 0.72, 1.70) (Figure). Twelve of the 22 AML cases occurred in pts who were RAEB-1 and 5 cases were diagnosed by anti-AML treatment alone (Table). In LTFU, pt-reported rates of MDS therapy use (e.g., azacitidine, cyclosporine, and romiplostim) were romiplostim: 31.1%, PBO: 23.2%. Reported rates of AML therapy use (e.g., azacitidine and chemotherapy) were romiplostim: 6.0%, PBO: 7.2%. A retrospective review of all available bone marrow aspirates and biopsies, including samples from pts diagnosed as having progressed to AML, was conducted by an independent hematopathologist; analyses are ongoing. Conclusion: Following the 2011 decision to stop study drug, study results have been updated with more time on study. Specifically, with the additional AML cases in the PBO arm during the 58-wk study period and data from the LTFU period, the HRs for progression to AML were 1.20 and 1.15, respectively, in contrast with the finding of a year ago (HR of 2.51 for 58-wk). As LTFU continues, additional data will be evaluated. Safety concerns regarding risk of disease progression to AML are still being investigated. Disclosures: Kantarjian: Amgen: Research Funding. Off Label Use: The use of romiplostim in MDS was examined in this trial. Mufti:Celgene: Consultancy, Research Funding. Fenaux:GlaxoSmithKline: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Amgen: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Kuendgen:Celgene: Honoraria. Gaidano:Amgen: Honoraria. Wiktor-Jedrzejczak:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy; Janssen-Cilag: Consultancy; Celgene: Speakers Bureau; Genzyme: Speakers Bureau; Genopharm: Speakers Bureau. Bennett:Onconova: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Ambit: Consultancy; Pfizer: Consultancy; Celgene: Consultancy. Meibohm:Merck: Employment, Equity Ownership; Amgen: Consultancy; Ockham: Employment. Yang:Amgen: Employment, Equity Ownership. Giagounidis:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Treatment With Romiplostim, a Thrombopoietin-Receptor Agonist, In Thrombocytopenic Patients With Low Or Intermediate-1 Risk Myelodysplastic Syndrome: Updated Follow-Up Results For Acute Myeloid Leukemia and Survival From a Randomized, Double-Blind, Placebo-Controlled Study

Blood ◽

10.1182/blood.v122.21.1553.1553 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1553-1553 ◽

Cited By ~ 3

Author(s):

Hagop M. Kantarjian ◽

Ghulam J. Mufti ◽

Pierre Fenaux ◽

Mikkael A. Sekeres ◽

Jeffrey Szer ◽

...

Keyword(s):

Placebo Group ◽

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Controlled Study ◽

Advisory Committees ◽

Long Term Follow Up

Abstract Background Thrombocytopenia in myelodysplastic syndrome (MDS) occurs in approximately 50% of patients with low/intermediate-1 MDS and is associated with reduced survival; few therapies are available. In a randomized placebo-controlled study, 250 patients with MDS were randomized 2:1 to receive weekly romiplostim or placebo. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events (HR 0.83, 95% CI: 0.66, 1.05, P = 0.13) and platelet transfusions (RR 0.77, 95% CI: 0.66, 0.88), and increased IWG HI-P incidence (OR 15.6, 95% CI: 4.7, 51.8). Increases in peripheral blast counts to >10% were more frequent with romiplostim (25/167, 15%) than placebo (3/83, 3.6%), and in most cases resolved after discontinuation. Due to concerns of the data monitoring committee that the potential benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to acute myeloid leukemia (AML) and that transient increases in blast cell counts might put patients at risk for diagnosis of and treatment for AML, treatment with study drug was discontinued in February 2011. Patients were then moved into the long-term follow-up (LTFU) portion of the study. Previously reported (July 2012) 58-week incidence of AML was romiplostim: 6.0% (10 patients), placebo: 4.9% (4 patients), HR 1.20 (95% CI: 0.38, 3.84). This report provides data on long-term follow-up of these patients to March 2013, with a particular emphasis on AML incidence. Methods Eligible patients had IPSS low/intermediate-1 MDS and platelets 1) ≤20x109/L or 2) ≤50x109/L with a history of bleeding, and were receiving only supportive care. Disease progression to AML was defined as 1) ≥20% blasts in the bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim, 2) pathology consistent with leukemia including chloroma or leukemia cutis, or 3) anti-leukemic treatment initiation. Results are presented by treatment group. Results Of 250 patients in the study, 210 entered LTFU, and 98 of these patients remained on study as of March 2013; the median (Q1, Q3) follow-up was 25.5 (10.8, 33.1) months. Reasons for discontinuation during LTFU were similar in the romiplostim and placebo groups: death (46.7%, 98 patients); lost to follow up (4.8%, 10 patients), and consent withdrawal (1.9%, 4 patients). During the active study period or during LTFU, death was reported in 44.3% (74 patients) in the romiplostim group and 44.6% (37 patients) in the placebo group (HR 1.04, 95% CI: 0.70, 1.54) (Figure). AML was reported in 10.7% (18 patients) in the romiplostim group and 9.8% (8 patients) in the placebo group (HR 1.14, 95% CI: 0.49, 2.62) (Figure). The proportions of patients who either died or developed AML were 46.1% (77 patients) in the romiplostim group and 45.8% (38 patients) in the placebo group (HR 1.07, 95% CI: 0.72, 1.58). Thirteen of the 26 AML cases occurred in patients who were RAEB-1 and 5 cases were diagnosed by anti-AML treatment alone (Table). In LTFU, patient-reported use of MDS therapy (e.g., azacitidine or cyclosporine) in the romiplostim group was 40.6% and in the placebo group, 28.2%. Reported use of AML therapy (e.g., chemotherapy) was 8.8%, romiplostim and 7.0%, placebo. Conclusion Following the 2011 decision to stop study drug, results have been updated with more observational time on study. Specifically, the HRs for death or progression to AML are 1.04 and 1.14, respectively, compared with 2012 HRs of 1.09 (95% CI: 0.71, 1.68) and 1.15 (95% CI: 0.47, 2.85) respectively. In LTFU, more patients in the romiplostim group than in the placebo group received MDS therapy. As LTFU continues, additional data will be evaluated. Safety concerns regarding risk of disease progression to AML are still being investigated. Disclosures: Kantarjian: Amgen Inc.: Research Funding. Off Label Use: Romiplostim is indicated for treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Treatment of thrombocytopenia due to MDS, which is the subject of a study described in this abstract, is not an approved indication. Mufti:Novartis: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Amgen: Speakers Bureau. Fenaux:Amgen Inc.: Research Funding. Sekeres:Amgen Inc.: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Szer:Alexion Australia: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Sandoz: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Platzbecker:Amgen Inc.: Honoraria. Kuendgen:Celgene: Research Funding. Gaidano:Amgen Inc.: Consultancy, Honoraria. Wiktor-Jedrzejczak:Amgen Inc.: Research Funding. Meibohm:Amgen Inc.: Consultancy. Lopez:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.

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Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-116496 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2149-2149

Author(s):

Romil Patel ◽

Neeraj Y Saini ◽

Ankur Varma ◽

Omar Hasan ◽

Qaiser Bashir ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Advisory Committees ◽

First Remission ◽

Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All "Non-Adverse" Risk AML

Blood ◽

10.1182/blood-2020-142691 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Gavin Hui ◽

Abdullah Ladha ◽

Edna Cheung ◽

Caroline Berube ◽

Steven Coutre ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Gemtuzumab Ozogamicin ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Monosomy 7

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

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